Compositions and methods of treating cancer

Abstract

This present invention compositions and methods of treating cancer and methods of accessing/monitoring the responsiveness of a cancer cell to a therapeutic compound.

1 . A method of treating cancer in a subject comprising
 a) determining whether said cancer cell is deficient in a DNA repair pathway and;   b) administering a DNA damaging agent or inhibitor specific for at least one different DNA repair pathway than that identified in step (a) to said subject.   
     
     
         2 . A method of treating cancer in a subject comprising
 a) determining whether said cancer cell is deficient in a DNA repair pathway   b) identifying a DNA repair pathway protein or gene that is upregulated in said cancer cell and;   c) administering a DNA damaging agent or inhibitor specific for said DNA repair pathway protein or gene identified in step (b) to said subject.   
     
     
         3 . The method of  claim 2 , further comprising administering a DNA damaging agent or inhibitor specific for at least one different DNA repair pathway than that identified in step (a) to said subject. 
     
     
         4 . The method of  claim 1 , wherein said cancer cell is deficient in a homologous recombination and crosslinking repair (FA/HR) DNA repair pathway and said agent is specific for the mismatch repair (MMR) DNA repair pathway or the non-homologous endjoining repair (NHEJ) DNA repair pathway. 
     
     
         5 . The method of  claim 4 , wherein said agent specific for NHEJ is a ATM inhibitor or a DNAPKcs inhibitor. 
     
     
         6 . The method of  claim 1 , wherein said cancer cell is deficient in the mismatch repair (MMR) DNA repair pathway or the non-homologous endjoining repair (NHEJ) DNA repair pathway and said agent is specific for the a homologous recombination and crosslinking repair (FA/HR) DNA repair pathway. 
     
     
         7 . The method of  claim 1 , wherein said DNA damaging agent is selected from the group consisting of a crosslinking agent, a strand break agent, an alkylating agent, an anti-metabolite agent, a microtubule disrupter, a radiomimetic agent, a radiosensitizer, an intercalator, a DNA replication inhibitor, an anthracyclines, an etoposide, and a topoisomerase II inhibitor 
     
     
         8 . A method for selecting a therapeutic agent for a particular cancer cell comprising
 a) determining a deficiency in one or more DNA repair pathways in said cancer cell relative to a normal cell and;   b) selecting a DNA damaging agent or inhibitor specific for at least one DNA repair pathway other than the DNA pathway identified in step (a).   
     
     
         9 . A method of determining the resistance of a cancer cell to a chemotherapeutic agent comprising identifying a deficiency in a DNA repair pathway, wherein the presence of said deficiency indicates said cell is resistant to a chemotherapeutic agent specific for said DNA repair pathway. 
     
     
         10 . A method of determining the sensitivity of a cancer cell to a chemotherapeutic agent comprising identifying a deficiency in a DNA repair pathway, wherein the absence of said deficiency indicates said cell is sensitive to a chemotherapeutic agent specific for said DNA repair pathway. 
     
     
         11 . The method of  claim 1 , wherein said deficiency is determined by measuring the expression of a DNARMARKER. 
     
     
         12 . The method of  claim 1 , wherein said deficiency is determined by detecting a mutation in a DNARMARKER. 
     
     
         13 . The method of  claim 1 , wherein said deficiency is determined by detecting a post translation modification of a DNARMARKER. 
     
     
         14 . The method of  claim 13 , wherein said post translational modification is selected from the group consisting of phosphorylation, ubiquitination, sumo-ylation, acetylation, alkylation, methylation, glycylation, glycosylation, isoprenylation, lipoylation, phosphopantetheinylation, sulfation, selenation and C-terminal amidation. 
     
     
         15 . The method of  claim 1 , wherein said DNA repair pathway is selected from the group consisting: base excision repair (BER), homologous recombination and crosslinking repair (FA/HR), mismatch repair (MMR), non-homologous endjoining repair (NHEJ), nucleotide excision repair (NER), translesion DNA synthesis (TLS), and DNA damage response controls (DDR). 
     
     
         16 . A method of identifying the responsiveness of a cancer cell to a DNA crosslinking agent or ionizing radiation comprising identifying a deficiency in the homologous recombination and crosslinking repair (FA/HR) DNA repair pathway, wherein the presence of said deficiency indicates said cell is sensitive to DNA cross linking agent or ionizing radiation, whereas an absence if said efficiency indicates said cell is resistant to DNA crosslinking agent or ionizing radiation. 
     
     
         17 . The method of  claim 16 , wherein said cross-linking agent is cisplatin, carboplatin, oxalipatin, mitomycin C or melphalan. 
     
     
         18 . The method of  claim 16 , wherein said deficiency in the FA/HR DNA repair pathway is determined by detecting monoubiquitination of FANCD2. 
     
     
         19 . A method of increasing the responsiveness of a cancer cell to a DNA crosslinking agent or ionizing radiation comprising contacting said cancer cell with an inhibitor of the homologous recombination and crosslinking repair (FA/HR) DNA repair pathway. 
     
     
         20 . The method of  claim 19 , wherein said cross-linking agent cisplatin, carboplatin, oxalipatin, mitomycin C or melphalan. 
     
     
         21 . The method of  claim 19 , wherein said inhibitor is a MAP2KAP2 inhibitor or a FA/HR DNA repair pathway inhibitor. 
     
     
         22 . A method of identifying the responsiveness of a cancer cell to a MAP2KAP2 inhibitor comprising detecting phosphorylation of MAP2KAP2, wherein the presence of said phosphorylation indicates said cell is sensitive to a MAP2KAP2 inhibitor, whereas an absence of said phosphorylation indicates said cell is resistant to a MAP2KAP2 inhibitor. 
     
     
         23 . A method of identifying the responsiveness of a cancer cell to a FA/HR DNA repair pathway inhibitor comprising identifying a deficiency in the mismatch repair (MMR) DNA repair pathway, wherein the presence of said deficiency indicates said cell is sensitive to a FA/HR DNA repair pathway inhibitor whereas an absence if said efficiency indicates said cell is resistant to a FA/HR DNA repair pathway inhibitor. 
     
     
         24 . The method of  claim 23 , wherein said FA/HR DNA repair pathway inhibitor is curcumin, velcade or alsterpaulone. 
     
     
         25 . A method of monitoring the treatment of a subject with cancer comprising
 a) detecting the level of an effective amount of two or more DNARMARKERS selected from the group consisting of DNARMARKERS1-259 in a first sample from the subject at a first period of time;   b) detecting the level of an effective amount of two or more DNARMARKERS in a second sample from the subject at a second period of time;   c) comparing the level of the effective amount of the two or more DNARMARKERS detected in step (a) to the amount detected in step (b), or to a reference value.   
     
     
         26 . A method of accessing the effectiveness of a treatment of a subject with cancer comprising
 a) measuring the level of an effective amount of two or more DNARMARKERS selected from the group consisting of DNARMARKERS1-259 in a sample from the subject, and   b) comparing the level of the effective amount of the two or more DNARMARKERS to a reference value.   
     
     
         27 . A method of monitoring the treatment of a subject with cancer comprising
 a) determining whether said cancer cell is deficient in a DNA repair pathway at a first period of time;   b) determining whether said cancer cell is deficient in said DNA repair pathway identified in step (a) at a second period of time;   wherein a decrease in said deficiency in said DNA repair pathway indicates said treatment is not efficacious, whereas a increase or no change in said DNA repair pathway indicates said treatment is efficacious   
     
     
         28 . A panel comprising at least two proteins selected from two or more DNA repair pathways selected from the group consisting of: base excision repair (BER), homologous recombination and crosslinking repair (FA/HR), mismatch repair (MMR), non-homologous endjoining repair (NHEJ), nucleotide excision repair (NER), translesion DNA synthesis (TLS), and DNA damage responsiveness (DDR). 
     
     
         29 . The panel of  claim 28 , wherein said BER pathway proteins are selected from the group consisting of: hOGG1, hNTH1, hNEIL1, hNEIL2, hNEIL3, AAG, UNG1, TDG, MUTY, MTH1, MBD4, APE1, XPG, DNAPOLβ, XRCC1, PARP1, DNAPOLδ1, DNAPOLδ2, DNAPOLδ3, DNAPOLδ4, DNAPOLδ5, DNAPOLε1, DNAPOLε2, DNAPOLε3, DNAPOLε4, DNAPOLε5, DNALigase1, PCNA, UBC13, MMS2, FEN1, RFC1, RFC2, RFC3, RFC4, RFC5, DNALigase1, DNAligase3, and Aprataxin (Aptx). 
     
     
         30 . The panel of  claim 28 , wherein said HR pathway proteins are selected from the group consisting of: XRCC1, PARP1, FEN1, DNA ligase1, SNM1, H2A, RPA1, RPA2, RPA3, RAD51, XRCC2, XRCC3, RAD51L1, RAD51L2, RAD51L3, DMC1, RAD52, RAD54, MUS81, MMS4, EMSY, BRCA1, BARD1, BLM, BLAP75, SRS2, SAE2, and ERCC1. 
     
     
         31 . The panel of  claim 28 , wherein said HR/FA pathway proteins are selected from the group consisting of: TRF2, BRCA2/FANCD1, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL, FANCM, hHef1, FANCI, USP1, and PALB2/FANCN. 
     
     
         32 . The panel of  claim 28 , wherein said MMR pathway proteins are selected from the group consisting of: DNMT1, hMLH1, hPMS2, hPMS1, GTBP (hMSH6), hMSH2, hMSH3, HMGB1, MSH4, MSH5, EXO1, DNAPOLδ1, DNAPOLδ2, DNAPOLδ3, DNAPOLδ4, DNAPOLδ5, DNAPOLε1, DNAPOLε2, DNAPOLε3, DNAPOLε4, DNAPOLε5, DNA Ligase I, PCNA, RPA1, RPA2, RPA3, and MUTY. 
     
     
         33 . The panel of  claim 28 , wherein said DDR pathway proteins are selected from the group consisting of: MRE11, RAD50, NBS1, H2A, ATM, P53, SMC1, ATF2, CHK1, CHK2, MAPKAP Kinase2, RPA1, RPA2, RPA3, RAD17, RFC1, RFC2, RFC3, RFC4, RFC5, RAD9, RAD1, HUS1, ATRIP, ATR, MDC1, CLASPIN, TOPB1, BRCC36, BLM, SRS2, SAE2, P53BP1, ING1, ING2, SMC1, BLAP75, BACH1, BRCA1, BRCA2, BARD1, RAP80, Abraxas, CDT1, RPB8, PPM1D, GADD45, DTL/CDT2, HCLK2, CTIP, BAAT1, HDM2/MDM2, APLF (aprataxin- and PNK-like factor), 14-3-3 σ, Cdc25A, Cdc25B, Cdc25C, and PBIP1. 
     
     
         34 . The panel of  claim 28 , wherein said NER pathway proteins are selected from the group consisting of: H2A, XPC, HR23A, HR23B, DDB1, DDB2, XPD, XPB, XPG, CSA, CSB, XPA, XPF, ERCC1, RNAPolymerase2, GTF2H1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, MNAT1, MAT1, CDK7, CyclinH, PCNA, RFC1, RFC2, RFC3, RFC4, RFC5, DNAPOLδ1, DNAPOLδ2, DNAPOLδ3, DNAPOLδ4, DNAPOLδ5, DNAPOLε1, DNAPOLε2, DNAPOLε3, DNAPOLε4, DNAPOLε5, and DNALigaseI. 
     
     
         35 . The panel of  claim 28 , wherein said TLS pathway proteins are selected from the group consisting of: DNAPOLη, DNAPOLτ, DNAPOLκ, REV1, DNAPOLζ, DNAPOLθ, PCNA, UBC13, MMS2, RAD5, hRAD6A, hRAD6B, RAD18, WRN, and USP1. 
     
     
         36 . The panel of  claim 28 , wherein said NHEJ pathway proteins are selected from the group consisting of: SIRT6, H2A, ARP4, ARP8, Ino80, SWR1, KU70, KU80, DNAPKcs, Artemis, PSO2, XRCC4, DNA LIGASE4, XLF, DNAPOLλ, PNK, METNASE, and TRF2. 
     
     
         37 . The panel of  claim 28 , further comprising at least one protein selected from the group consisting of MGMT, TDP1, DNAPOLμ, hABH1, hABH2, hABH3, hABH4, hABH5, hABH6, hABH7, hABH8, TOPO1, TOPOII, UBC9, UBL1, and MMS21. 
     
     
         38 . A panel comprising at least one Fanconi Anemia protein and at least one Mismatch Repair protein. 
     
     
         39 . The panel of  claim 38 , further comprising a DNAPKPcs protein or PARP. 
     
     
         40 . The panel of  claim 38 , wherein said Fanconi Anemia protein is selected from the group consisting of: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL, and FANCM. 
     
     
         41 . The panel of  claim 38 , wherein said Mismatch Repair protein is selected from the group consisting of: MLH1, MSH2, MSH3, MSH4, MSH5, and MSH6 
     
     
         42 . A panel comprising one or more DNARMARKERS that are indicative of a pathway associated to DNA repair or DNA damage recognition and regulatory proteins. 
     
     
         43 . An array comprising a plurality of detection reagents that detect the panel of  claim 28 .